Discovery of Benzimidazole Derivatives as Novel Aldosterone Synthase Inhibitors:QSAR,Docking Studies,and Molecular Dynamics Simulation

• 作者: GUO Hong-Mei YU Na FU Le LI Guang-Ping SHU Mao LIN Zhi-Hua
• 来源期刊: 结构化学
• 年，卷（期）: 2022,（3）
• 页码范围: 193-210
• 页数: 18页
• 语种: 英文
• DOI: 10.14102/j.cnki.0254-5861.2011-3321

摘要

Aldosterone synthase inhibitors can lessen the production of aldosterone in organisms,which effec-tively affecting the treatment of hypertension.A series of computational approaches like QSAR,docking,DFT and molecular dynamics simulation are applied on 40 benzimidazole derivatives of aldosterone synthase(CYP11B2)in-hibitors.Statistical parameters:Q2=0.877,R2=0.983(CoMFA)and Q2=0.848,R2=0.994(CoMSIA)indicate on good predictive power of both models and DFT's result illustrates the stability of both models.Besides,Y-randomization test is also performed to ensure the robustness of the obtained 3D-QSAR models.Docking studies show inhibitors rely on π-π interaction with residues,such as Phel30,Ala313 and Phe481.Molecular dynamics simulation results further confirm that the hydrophobic interaction with proteins enhances the inhibitor's inhibitory effect.Based on QSAR studies and molecular docking,we designed novel compounds with enhanced activity against aldosterone synthase.Furthermore,the newly designed compounds are analyzed for their ADMET proper-ties and drug likeness and the results show that they all have excellent bioavailability.